Pablo Sabucedo ^1,2 Oscar Andión ³ Robert A Neimeyer ⁴ Oscar Soto ^2,5,6,7 Julia Javkin ^10,2,8,9 Josep Maria Haro ^11,12,5 Magi Farre ^13,14 Débora González ^10,15,2,6*

• ¹ Faculty of Health and Life Sciences, University of Liverpool, Liverpool, North West England, United Kingdom
• ² Sociedad Española de Medicina Psicodélica (SEMPsi), Barcelona, Balearic Islands, Spain
• ³ Research Sherpas, Girona, Spain
• ⁴ Portland Institute for Loss and Transition, Portland, United States
• ⁵ Parc Sanitari Sant Joan de Déu, España, Spain
• ⁶ Fundació Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Barcelona, Balearic Islands, Spain
• ⁷ Department of Psychiatry and Forensic Medicine, School of Medicine, Autonomous University of Barcelona, Barcelona, Catalonia, Spain
• ⁸ Kiyumi collective, Hoosfdorp, Netherlands
• ⁹ Heart & brain training, Nijmegen, Netherlands
• ¹⁰ PHI Association, Barcelona, Spain, Barcelona, Balearic Islands, Spain
• ¹¹ Fundació Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
• ¹² Center for Biomedical Research in Mental Health Network (CIBERSAM), Madrid, Madrid, Spain
• ¹³ Department of Clinical Pharmacology, Hospital Universitari Germans Trias I Pujol-IGTP, Badalona, Spain
• ¹⁴ Departament of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, Barcelona, Spain
• ¹⁵ Faculty of Health Sciences, University Isabel I, Burgos, Spain

Background. Psychotherapy for Prolonged Grief Disorder (PGD), a condition characterized by an intense and persistent grief response, has received increased attention over the past decades. Evidence-based approaches to prevent PGD are currently scarce, and not always effective. This paper introduces a protocol for a clinical trial exploring the effectiveness of a Meaning Reconstruction psychotherapy approach (MR) assisted with ayahuasca, a traditional indigenous medicine. Method. The outlined protocol is a three-arm, non-randomized controlled trial focused on reducing normal and pathological grief symptoms, comparing the effectiveness of Ayahuasca-assisted MR therapy (A-MR), MR therapy alone (MR) and No Treatment (NT). At least 69 people who lost a first-degree relative during the prior year, and with a Texas Revised Inventory of Grief score up 39 (TRIG ≥ 40), will participate in the trial. Participants will be allocated to an A-MR (n ≥ 23), MR (n ≥ 23) or NT (n ≥ 23) group. Those from the A-MR and MR therapy groups will undergo a therapeutic process involving 9 sessions of online psychotherapy. In addition, the A-MR condition involves 2 group sessions of ayahuasca. The primary outcomes will be normal and pathological grief severity as measured by the TRIG and Traumatic Grief Inventory Self-Report (TGI-SR), administered at baseline, post-treatment, and 3-month follow up. Measures of quality of life, post-traumatic growth, meaning-made, psychological flexibility, and self-belief consistency will be also included. In addition, subjective effects of ayahuasca and acceptance-avoidance promoting effects will be assessed following ayahuasca administration. Finally, we will analyze the potential mediating effect of meaning-made, psychological flexibility and self-belief consistency in grief symptoms (as measured by the TRIG and TGI). Discussion. This trial is the first to empirically examinate the potential of psychedelic-assisted psychotherapy for grief, as well as the potential processes of change that may account for it.